Goals and Health Relatedness: This predoctoral NRSA proposal seeks support for research career development in the emerging, biomedically important field of "vascular aging." The career goal of the candidate, Ms. Jablonski, is to become an independent investigator in translational research focusing on the mechanisms mediating vascular aging in humans and interventions that prevent or reverse vascular aging. The proposed research project has important clinical implications for the prevention of cardiovascular diseases (CVD) because vascular aging is a major risk factor for CVD. Research Project: This project will determine the efficacy of dietary sodium restriction (DSR) to improve vascular endothelial function, a key expression of vascular aging, as assessed by endothelium-dependent dilation (EDD). Declines in EDD are predictive of atherosclerosis and CVD events. Aging and increased systolic blood pressure (SBP) markedly reduce EDD. The factors implicated are incompletely understood, but dietary sodium intake may be involved. Arterial blood pressure sensitivity to salt increases with age and high salt intake is associated with vascular dysfunction. Recently our laboratory demonstrated that DSR improves carotid artery compliance in middle-aged and older adults (MA/O) with elevated SBP. However, the efficacy of DSR for improving EDD in this group is unknown. To address this issue, MA/0 with elevated SBP will be studied under conditions of normal and low sodium diet (randomized, double-blind, placebo controlled cross-over design). The influence of DSR on EDD will be evaluated using brachial artery flow-mediated dilation (FMD) and the forearm blood flow (FBF) response to an intrabrachial infusion of acetylcholine (ACh). The potential mechanistic roles of reductions in oxidative stress and increases in nitric oxide (NO) bioavailability and bioactivity of tetrahydrobiopterin (BH4), a critical cofactor for NO synthesis by endothelial NO synthase (eNOS), also will be determined. Insight into the cellular and molecular mechanisms involved in changes in EDD with DSR will be gained from measurements of protein expression of potential mediators analyzed from human peripheral blood mononuclear cells (PBMCs) and vascular endothelial cells. The proposed research project has important public health relevance, as CVD remains a/the leading cause of illness and death in the U.S. MA/O adults are at increased risk of CVD. As such, establishing the efficacy of lifestyle interventions that restore EDD in MA/O with elevated SBP and the integrative physiological mechanisms involved are clinically imperative, particularly given projections for the increasing number of older adults in the future. Finally, this research project and training plan will provide an outstanding platform for research career development.